Agents and methods for enhancing photodynamic therapy

Abstract

A chemical conjugate for administration to a patient undergoing photodynamic therapy includes a photoactive compound coupled to a leakage reducing agent that is structured to reduce leakage of the photoactive compound from a patient's vasculature. The leakage reducing agent may be a bulking agent to reduce, for example, sterically reduce, the permeability of the photoactive compound through the blood vessel, or it may be a ligand that binds to endothelial cells of a patient's choriocapillaries. The conjugate may be used in methods of reducing secondary damage associated with photodynamic therapy.

1 . A conjugate for reducing secondary damage associated with laser treatment of choroidal neovascularization, the conjugate comprising a photoactive compound coupled to a bulking agent so that the size of the conjugate is greater than the size of the photoactive compound without the bulking agent, and the size is sufficient to reduce permeability of the photoactive compound from a blood vessel of a patient after the conjugate is administered to the patient relative to the permeability of the photoactive compound from a blood vessel of a patent after the photoactive compound without the bulking agent is administered to the patient.  
   
   
       2 . The conjugate of  claim 1 , wherein the photoactive compound comprises a porphyrin.  
   
   
       3 . The conjugate of  claim 1 , wherein the photoactive compound comprises verteporfin.  
   
   
       4 . The conjugate of  claim 1 , wherein the photoactive compound is selected from a group consisting of hematoporphyrins, hematoporphyrin derivatives, pheophorbides, derivatives of pheophorbides, bacteriochlorins, purpurins, merocyanines, porphycenes, and combinations thereof.  
   
   
       5 . The conjugate of  claim 1 , wherein the bulking agent comprises a lipid.  
   
   
       6 . The conjugate of  claim 1 , wherein the bulking agent comprises a fatty acid.  
   
   
       7 . The conjugate of  claim 1 , wherein the bulking agent comprises a carbohydrate.  
   
   
       8 . The conjugate of  claim 7 , wherein the bulking agent comprises a polysacharide.  
   
   
       9 . The conjugate of  claim 8 , wherein the bulking agent comprises a dextran.  
   
   
       10 . The conjugate of  claim 1 , wherein the bulking agent is covalently coupled to the photoactive compound.  
   
   
       11 . The conjugate of  claim 1 , further comprising a linker between the photoactive compound and the bulking agent.  
   
   
       12 . The conjugate of  claim 11 , wherein the linker is covalently bonded to the bulking agent and the photoactive compound.  
   
   
       13 . The conjugate of  claim 11 , wherein the linker is structured to augment distribution of the photoactive compound within the vasculature of the patient.  
   
   
       14 . The conjugate of  claim 11 , wherein the linker is structured to augment quenching of the photoactive compound when electromagnetic energy is applied to the photoactive compound.  
   
   
       15 . The conjugate of  claim 1  in a pharmaceutical composition.  
   
   
       16 . The conjugate of  claim 1 , wherein the conjugate has a molecular weight of between about 60 kilodaltons and about 120 kilodaltons.  
   
   
       17 . A method for reducing secondary damage associated with laser treatment of choroidal neovascularization, comprising a step of: 
 administering a conjugate to a patient having a choroidal neovascularization, the conjugate comprising a photoactive compound coupled to a bulking agent that is sized to reduce permeability of the photoactive compound through a blood vessel of the patient to reduce the amount of the photoactive compound outside of the blood vessel when electromagnetic energy from a laser is applied to the choroidal neovascularization relative to administering the photoactive compound without the bulking agent to the patient.    
   
   
       18 . The method of  claim 17 , wherein the step of administering the conjugate comprises systemic administration.  
   
   
       19 . The method of  claim 17 , wherein the step of administering the conjugate comprises topical administration.  
   
   
       20 . The method of  claim 19 , further comprising a step of administering a permeability enhancing agent to the patient to enhance the topical administration of the conjugate to the patient relative to a similar method without administering a permeability enhancing agent to the patient.  
   
   
       21 . The method of  claim 17 , wherein the step of administering the conjugate is performed at a time sufficiently before the electromagnetic energy is applied to the choroidal neovascularization to permit the conjugate to accumulate in the choroidal neovasculature.  
   
   
       22 . A conjugate for reducing secondary damage associated with laser treatment of choroidal neovascularization, comprising: 
 a photoactive compound structured to absorb energy emitted from a laser; and    a leakage reducing agent coupled to the photoactive compound, the leakage reducing agent being structured to reduce leakage of the photoactive compound from a choriocapillary in an eye of a patient into the choriocapillaris of the eye of the patient after the conjugate has been administered to the patient relative to after the photoactive compound without the leakage reducing agent has been administered to the eye.    
   
   
       23 . The conjugate of  claim 22 , wherein the photoactive compound comprises a porphyrin.  
   
   
       24 . The conjugate of  claim 22 , wherein the photoactive compound comprises verteporfin.  
   
   
       25 . The conjugate of  claim 22 , wherein the photoactive compound is selected from a group consisting of hematoporphyrins, hematoporphyrin derivatives, pheophorbides, derivatives of pheophorbides, bacteriochlorins, purpurins, merocyanines, porphycenes, and combinations thereof.  
   
   
       26 . The conjugate of  claim 22 , wherein the leakage reducing agent comprises a bulking agent that is sized to sterically reduce movement of the photoactive compound from the microcapillary to the choriocapillaris of the patient.  
   
   
       27 . The conjugate of  claim 26 , wherein the leakage reducing agent comprises a bulking agent selected from a group consisting of fatty acids, lipids, and carbohydrates.  
   
   
       28 . The conjugate of  claim 22 , wherein the leakage reducing agent comprises a ligand that specifically binds to endothelial cells of the choriocapillaries of the patient.  
   
   
       29 . The conjugate of  claim 22 , wherein the leakage reducing agent comprises a tripeptide motif of the amino acid sequence RGD.  
   
   
       30 . The conjugate of  claim 22 , wherein the leakage reducing agent comprises an integrin.  
   
   
       31 . The conjugate of  claim 22 , wherein the leakage reducing agent comprises Sialyl Lewis X.